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A series of 2-hetaryl- and 2-(hetaryl)ylidene substituted 5-fluoro-8-nitro-1,3-benzothiazin-4-ones was synthesized by interaction of 2,6-difluoro-3-nitrobenzoylisothiocyanate with C-nucleophiles. Cyclocondensation of polyfluorobenzoylchlorides with aryl and hetaryl thioamides represents new approach to 1,3-benzothiazin-4-ones. Some compounds proved to be promising for further development of tuberculostatic agents.

Tuberculosis remains a major public health problem, especially in developing countries. Brazil presents the largest number of cases in Latin America and is among the 22 countries considered priorities by the World Health Organization (WHO). The Rio de Janeiro state has the largest number of cases registered in the country. The treatment of patients, commonly, makes use of the drugs isoniazid and rifampicin for six months. This study aimed to develop and validate an electroanalytical methodology, using the technique of differential pulse voltammetry for the determination of these drugs in the associated form, in order to evaluate the quality of medicines distributed in the state of Rio de Janeiro. The potential reduction for the isoniazid and rifampicin were -1.10 and -0.90 V. The developed and validated electroanalytical method presented a linear range of 0.25 to 1.25 mg/L to isoniazid, limits of detection and quantification of 0.05 and 0.14 mg/L, and recovery of 98.2 ± 0.4%; a tracking linear of 0.40 to 2.00 mg/L for rifampicin, with limits of detection and quantification of 0.07 and 0.19 mg/L and recovery of 95.8 ± 0.6%. Six lots of medicines from two pharmaceutical companies were analyzed. Only one of the samples showed unsatisfactory levels of rifampicin.A tuberculose continua sendo um importante problema de saúde pública, especialmente em países em desenvolvimento. O Brasil apresenta o maior número de casos da América Latina, estando entre os 22 países considerados prioritários nas ações de controle da doença pela Organização Mundial da Saúde (OMS). No Brasil, o Rio de Janeiro é o estado com o maior número de casos registrados no país. O tratamento de doentes com tuberculose faz uso dos fármacos isoniazida e rifampicina durante seis meses. O presente trabalho objetivou desenvolver e validar metodologia eletroanalítica, utilizando a técnica de voltametria de pulso diferencial, para a determinação desses dois princípios ativos na forma associada e avaliar a qualidade dos medicamentos distribuídos no estado do Rio de Janeiro. Os potenciais de redução para a isoniazida e rifampicina foram respectivamente -1,10 e -0,90 V. O método eletroanalítico desenvolvido e validado apresentou para a isoniazida faixa linear de 0,25 a 1,25 mg/L, limites de detecção e quantificação de 0,05 e 0,14 mg/L e recuperação de 98,2 ± 0,4%; para a rifampicina faixa linear de 0,40 a 2,00 mg/L, limites de detecção e quantificação de 0,07 e 0,19 mg/L e recuperação de 95,8 ± 0,6%. Foram analisados 6 lotes de medicamentos de dois laboratórios farmacêuticos. Apenas uma das amostras apresentou teor de rifampicina insatisfatório.

In the current study we developed a micellar electrokinetic capillary chromatography method for the simultaneous determination of the most frequently used tuberculostatics isoniazid and rifampicin. The influence of pH, buffer concentration, surfactant concentrations, applied voltage, system temperature, injection parameters over the separation were studied as experimental variables. The optimal separation was carried out at 20°C and 25 kV, using a 25 mM borate buffer and 50 mM sodium dodecyl sulfate SDS at pH of 9.30. Under these conditions, the analysis was accomplished in about 3 minutes, the order of migration being isoniazid followed by rifampicin. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a contagious disease caused by the bacilli Mycobacterium tuberculosis complex. Currently, about a quarter of the world's population is infected with Mycobacterium tuberculosis . According to the World Health Organization, in 2018, Portugal had a TB incidence rate of about 24 cases per 100,000 inhabitants. It is estimated that 5-15% of individuals with latent TB infection progress to active TB. Isoniazid is one of the most widely used drugs for the treatment of active and latent TB. However, care must be taken with the possible development of toxicity, particularly hepatic. The authors report a case of a 60-year-old woman diagnosed with latent TB who started therapy with isoniazid. Five months later, she developed acute liver failure secondary to the drug, requiring liver transplantation, with a favorable clinical outcome. Thus, we intend to alert to the potential toxicities of isoniazid, establishing follow-up strategies in patients on this therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Almeida et al.)

series of forty-five derivatives of 3-phenyl-4-thioxo-2 H-1,3-benzoxazine-2(3 H)-ones and forty-five derivatives of 3-phenyl-2 H-1,3-benzoxazine-2,4(3 H)-dithiones was synthesised. The compounds exhibited in-vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains), and M. avium. The most active derivatives were more active than isonicotinhydrazide (INH). The quantitative relationships between the structure and antimycobacterial activity were calculated. The activity against M. tuberculosis increased with the lipophilicity of the substituents. [ABSTRACT FROM AUTHOR]

Abstract: Crystal structures of two title compounds and several their relatives known earlier reveal conservative and characteristic features, which may be related to their tuberculostatic activity. The molecules are predominantly planar due to conjugation through five successive bonds in the zwitterionic fragment S−–C(sp2)–N–NH+–C(sp2)–NH2 and intramolecular hydrogen bonds, which prevent rotation of the adjacent pyrazine (or pyridine) ring. It has been suggested that in spatial sense such planar molecules resemble acridines intercalating with nucleic acids and that similar process may be responsible for tuberculostatic activity of the title pyrazine-2-carboxamide-N′-carbonothioyl-hydrazones. [Copyright &y& Elsevier]

The reactions of o-phenylenediamine and 3,4-diaminotoluene with such acids as 3-cyclohexylpropionic, 4-phenylbutyric, 4-cyclohexylbutyric, 3,3-diphenylpropionic, and 3,4-dimethoxyphenylacetic resulted in the formation of the corresponding 2-substituted benzimidazoles. These compounds were transformed into methane-and benzenesulfonamide derivatives. The benzimidazole derivatives obtained were tested in vitro for their tuberculostatic activity. Compounds with good activity (MIC 6.2-25 µg/ml) have been found. [ABSTRACT FROM AUTHOR]

The N 1 -dithioester substituted pyridin- and pyrazincarboxamidrazones underwent cyclocondensation to 5-methylsulfanyl-1,3,4-thiadiazole or 1,2,4-triazole derivatives, depending on the reaction conditions. With an excess of secondary amines, pyrazincarboxamidrazone dithioester gave 5-amino-1,3,4-thiadiazoles and with an ethanoloamine a 1,2,4-triazole derivative. Prepared compounds were evaluated as potential tuberculostatic agents, but the minimum inhibitory concentrations values indicated no significant activity. [ABSTRACT FROM AUTHOR]

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In the reactions of S,S'-dimethyldithiocarbamate pyrazinoylhydrazone with diamines some 3-pyrazinyl-1,2,4-triazolo[4,3-a]-1,3-diazacycloalkanes were obtained, and the mechanism of their formation was proposed. The products were acylated, hydroxyalkylated, and aminomethylated. Their tuberculostatic activity was tested in vitro. [ABSTRACT FROM AUTHOR]

The synthesis of N'-[amino(6-chloro- and 6-cycloaminopyrazin-2-yl)methylene/carbodithioic acid mono- and diesters and their reactions are described Cyclization of monoesters with secondary amines in acidic media gave the 1,3, 4-thiadiazole derivatives, while the cyclization of diesters with amines yielded 1,2,4-triazoles with the amine substituent in position 3. The in vitro tuberculostatic activity of the prepared compounds was tested. [ABSTRACT FROM AUTHOR]

The series of derivatives of substituted N-pyridinylsalicylamides were synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. In the quantitative structure activity relationships analysis (QSAR), the Free–Wilson and Hansch approaches were used but the analysis was not significant. (The standard deviations of regression coefficients were greater than the values of the coefficients). The molecules were separated the heterocyclic and salicyl moiety in the molecules, and the study of influences of substituents on salicyl moiety was used, as well. 5-Chloro-pyridin-2-yl, and the substitution of the salicyl moiety by chlorine in position 4 or 5 had the strongest influence on the increase in antimycobacterial activity. [Copyright &y& Elsevier]

The antimycobacterial activity in six series of substituted 3-phenyl-2H-benzoxazine-2,4(3H)-dithiones and 3-(phenyl)-4-thioxo-2H-benzoxazine-2,4(3H)-diones has been studied using a quantum molecular similarity approach. The approach is based on the use of fragment self-similarity measures as new universal molecular descriptors applicable for the design of novel theoretical QSAR models. Using this approach it was possible to show that while traditional QSAR models were able to describe the activity only within each of the six sets of studied molecules individually, the proposed approach is much more general and a single universal QSAR model describing the activity of all the 39 studied molecules in all the studied series together was built. The replacement of the oxo group by the thioxo group in position 4 on the benzoxazine ring of the antitubercular 3-(phenyl)-2H-benzoxazine-2,4(3H)-diones increases the activity, as well as the similar replacement in position 2. [Copyright &y& Elsevier]

A series of derivatives of 3-benzyl-2H-benzoxazine-2,4(3H)-dione substituted in positions 6, 7 or 8 on the benzoxazine, and in positions 3 or 4 on the benzyl moiety was synthesized. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium avium and two strains of Mycobacterium kansasii. The disadvantage of the compounds is in their low solubility in water. The antimycobacterial activity of N-benzylsalicylamides correlates with that of 3-benzyl-2H-1,3-benzoxazin-2,4(3H)-diones and depends on the partition coefficients and electronic indexes. [Copyright &y& Elsevier]

A 10-year-old girl with cervical tuberculosis was treated with Isoniazid, Rimfampicin and Ethambutol. After 2 weeks of treatment a hepatotoxic reaction developed. Withdrawal of therapy resulted in complete clinical improvement and in normalization of all laboratory measurements. Treatment was restarted with Rifampicin, Pyrazinamid and Ethambutol. Liver enzyme levels were monitored weekly. Seven weeks after this three-drug regiment was started, all therapy was discontinued because of elevated liver enzyme levels. However, the patient died 2 weeks later of progressive fulminant hepatitis. [ABSTRACT FROM AUTHOR]

New quaternary ammonium salt-type compounds with lipophilic cholesterol and terpene moieties were synthesized. The compounds showed promising antibacterial and antimycobacterial activities. Those compounds containing the cholesterol moiety showed significant activity against Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecium. On the contrary, the antimycobacterial activity increased with the presence of the terpene unit in the molecule., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)